This invention relates to a novel class of compounds which exhibit analgesic activity upon parenteral administration.
Recently, endogenous substances having morphine-like properties have been extracted from mammalian brain or csf. These substances, named enkephalin, have been identified by Hughes et al., Nature, 258, 577 (1975) as pentapeptides having the following sequences:
H-Tyr-Gly-Gly-Phe-Met-OH PA1 H-Tyr-Gly-Gly-Phe-Leu-OH. PA1 R.sub.1 and R.sub.2 independently are hydrogen or C.sub.1 -C.sub.3 primary alkyl; PA1 R.sub.3 is C.sub.1 -C.sub.4 primary or secondary alkyl or --CH.sub.2 CH.sub.2 --S--CH.sub.3 ; PA1 R.sub.4 is hydrogen or C.sub.1 -C.sub.3 primary alkyl; PA1 R.sub.5 is hydrogen or C.sub.1 -C.sub.3 primary alkyl; PA1 Y is hydrogen or acetyl; and PA1 Z is ##STR4## --CH.sub.2 OH, or --CN; subject to the limitation that no more than one of R.sub.4 and R.sub.5 is C.sub.1 -C.sub.3 primary alkyl. PA1 Abu--.alpha.-aminobutyric acid PA1 Ala--alanine PA1 Cys--cysteine PA1 Gly--glycine PA1 Hse--homoserine PA1 Ile--isoleucine PA1 Leu--leucine PA1 Met--methionine PA1 Nle--norleucine PA1 Nva--norvaline PA1 Phe--phenylalanine PA1 Phe--NH.sub.2 --phenylalanine amide PA1 Phe-A--primary alcohol derivative of phenylalanine PA1 Phe-CN--nitrile derivative of phenylalanine PA1 Ser--serine PA1 Tyr--tyrosine PA1 Val--valine PA1 Ac--acetyl PA1 Me--methyl PA1 Et--ethyl PA1 Ip--ispropyl PA1 Pr--n-propyl PA1 Bu--n-butyl PA1 i-Bu--isobutyl PA1 t-Bu--t-butyl PA1 s-Bu--sec-butyl PA1 BOC---t-butyloxycarbonyl PA1 Bzl--benzyl PA1 DCC--N,N'-dicylohexylcarbodiimide PA1 HBT--1-hydroxybenzotriazole PA1 DMF--N,N-dimethylformamide PA1 TFA--trifluoroacetic acid PA1 THF--tetrahydrofuran PA1 DEAE--diethylaminoethyl PA1 H-L-Tyr-D-Ala-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-Phe-A; PA1 H-L-Tyr-D-Abu-Gly-L-Phe-CN; PA1 H-L-Tyr-D-Abu-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Nva-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Nva-Gly-L-Phe-A; PA1 H-L-Tyr-D-Val-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Val-Gly-L-Phe-CN; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Nle-Gly-L-Phe-A; PA1 H-L-Tyr-D-Leu-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Leu-Gly-L-Phe-CN; PA1 H-L-Tyr-D-Ile-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ile-Gly-L-Phe-A; PA1 H-L-Tyr-D-Ala-Gly-L-(N-Et)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-A; PA1 H-L-Tyr-D-Ala-Gly-L-(.alpha.-Me)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-(.alpha.-Et)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-CN; PA1 H-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-A; PA1 H-L-Tyr-D-Met-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Met-Gly-L-(N-Et)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Met-Gly-L-(N-Me)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Met-Gly-L-(N-Me)Phe-A; PA1 H-L-Tyr-D-Met-Gly-L-(N-Et)Phe-CN; PA1 H-L-Tyr-D-Met-Gly-L-(.alpha.-Et)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Met-Gly-L-(.alpha.-Pr)Phe-NH.sub.2 ; PA1 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr(Ac)-D-Ala-Gly-L-(N-Me)Phe-NH.sub.2 ; PA1 H-L-Tyr(Ac)-D-Nle-Gly-L-(.alpha.-Me)Phe-NH.sub.2 ; PA1 H-L-Tyr(Ac)-D-Abu-Gly-L-Phe-A; PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-Phe-NH.sub.2 ; PA1 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr(Ac)-D-Ala-Gly-L-Phe-CN; PA1 (N-Et)-L-Tyr-D-Abu-Gly-L-(N-Et)Phe-NH.sub.2 ; PA1 (N,N-di-Pr)-L-Tyr-D-Val-Gly-L-(.alpha.-Me)Phe-NH.sub.2 ; PA1 (N-Pr)-L-Tyr-D-Leu-Gly-L-(.alpha.-Et)Phe-NH.sub.2 ; PA1 (N,N-Di-Et)-L-Tyr-D-Met-Gly-L-(.alpha.-Pr)Phe-NH.sub.2 ; PA1 (N-Me,N-Et)-L-Tyr(Ac)-D-Nle-Gly-L-(.alpha.-Me)Phe-NH.sub.2 ; PA1 (N,N-Di-Me)-L-Tyr(Ac)-D-Ile-Gly-L-(.alpha.-Et)Phe-NH.sub.2 ; PA1 (N-Me)-L-Tyr(Ac)-D-Leu-Gly-L-(.alpha.-Me)Phe-CN; PA1 (N-Me)-L-Tyr(Ac)-D-Nva-Gly-L-(.alpha.-Pr)Phe-A; PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-(.alpha.-Me)Phe-NH.sub.2 ; PA1 (N-Et)-L-Tyr(Ac)-D-Abu-Gly-L-(.alpha.-Pr)Phe-NH.sub.2 ; PA1 (N-Pr)-L-Tyr(Ac)-D-Val-Gly-L-Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-(.alpha.-Me)Phe-CN; PA1 H-L-Tyr-D-Ala-Gly-L-(.alpha.-Me)Phe-A; PA1 H-L-Tyr-D-Ala-Gly-L-(.alpha.-Et)Phe-A; PA1 H-L-Tyr-D-Ala-Gly-L-(.alpha.-Pr)Phe-NH.sub.2 ; PA1 H-L-Tyr-D-Ala-Gly-L-(.alpha.-Pr)Phe-CN; PA1 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-(.alpha.-Et)Phe-A; PA1 (N,N-Di-Me)-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-NH.sub.2 ; PA1 (N,N-Di-Et)-L-Tyr-D-Ala-Gly-L-(N-Et)Phe-CN; PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-A; PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-(N-Me)Phe-NH.sub.2 ; PA1 (N,N-Di-Me)-L-Tyr-D-Val-Gly-L-(N-Me)Phe-NH.sub.2 ; PA1 (N,N-Di-Pr)-L-Tyr-D-Ala-Gly-L-(N-Pr)Phe-NH.sub.2 ; PA1 (N-Me)-L-Tyr-D-Ala-Gly-L-(.alpha.-Et)Phe-NH.sub.2 ; PA1 (N,N-Di-Me)-L-Tyr(Ac)-D-Ala-Gly-L-(N-Et)Phe-CN; PA1 (N,N-Di-Pr)-L-Tyr(Ac)-D-Met-Gly-L-(N-Me)Phe-A; PA1 (N-Et)-L-Tyr(Ac)-D-Met-Gly-L-(N-Pr)Phe-NH.sub.2 ; PA1 (N-Me)-L-Tyr(Ac)-D-Met-Gly-L-(.alpha.-Me)Phe-NH;
These compounds are referred to as methionine-enkephalin and leucine-enkephalin, respectively.
Although these compounds have been shown to exhibit analgesic activity in mice upon administration intracerebroventricularly [Buscher et al., Nature, 261, 423 (1976)], they are practically devoid of any useful analgesic activity when administered parenterally.
A novel class of compounds has now been discovered. These compounds exhibit significant and demonstrable analgesic activity when administered systemically. It is to this class of compounds that this invention is directed.